From genetic testing that identifies inherited cancer predispositions to molecular profiling of tumors and liquid biopsies that guide targeted therapies, advances in oncology are offering cancer patients greater hope and improved outcomes with each passing year.

Nearly one in three Americans expected to face a cancer diagnosis in their lifetime, so understanding the differences between these tests—such as when they are recommended and for whom they are recommended for—is key to navigating this rapidly evolving landscape.

The Jupiter Medical Center Anderson Family Cancer Institute provides a full continuum of advanced cancer care that begins with robust diagnostics that include genetic and tumor testing, says The Anderson Family Cancer Institute Director Dr. Jon S. Du Bois.

The JMC Cancer Genetics and High-Risk Cancer Program helps patients assess their risk for hereditary cancers, provides counseling and ongoing support, and focuses on developing individualized care and treatment plans tailored to each patient’s needs.

Du Bois calls molecular testing “an exploding area in oncology” that is leading to the development of cutting-edge, targeted therapies that can turn cancer cells off—reducing toxicity, preserving normal cells, and increasing survival rates.

Prior to joining JMC, Du Bois served as the medical director for the Massachusetts General Hospital Cancer Center at Emerson Hospital and as chief of the Division of Hematology/Oncology. Du Bois was also a clinical associate in medicine at Massachusetts General Hospital, Harvard Medical School.

GENETIC TESTING FOR HEREDITARY RISKS

Some cancer-causing gene variants, or mutations, can be inherited through DNA and passed from one generation to the next. The American Cancer Society recognizes 14 types of hereditary cancer syndromes, though researchers estimate that less than 10 percent of all cancers are linked to inherited genetic mutations. Also known as inherited or genetic cancer syndromes, these conditions are often recognizable within families. Doctors look for specific warning signs and family patterns to determine whether an inherited cancer syndrome may be present, including the following:

• EARLY ONSET: Cancers diagnosed at much younger ages than usual
• MULTIPLE DIAGNOSES: The same individual develops two or more primary cancer types
• RARE TYPES: Rare cancers or those that typically only affect one sex (for instance, male breast cancer)
• GENERATIONAL PATTERNS: The same or related cancers appearing across multiple generations

The most widely recognized genetic test for inherited cancer risk is the BRCA test—the first genetic test for cancer risk available for clinical use in 1996. BRCA1 and BRCA2 (short for breast cancer genes 1 and 2) normally act as the body’s natural defense to help prevent cancer by making proteins that repair damaged DNA. Everyone inherits a copy of tumor-suppressor genes from each parent. But when either gene contains a mutation, its protective function is compromised, increasing the risk of certain cancers.

Harmful mutations in the BRCA genes greatly increase the risk of breast and ovarian cancers. Another inherited condition, Lynch syndrome, is also caused by mutations in tumor-suppressor genes and raises the likelihood of developing colorectal, endometrial, and several other types of cancer.

“This area is booming. We have ability to test someone’s DNA—the blueprint of your genes from your parents—and look for mutations that increase lifetime risk,” says JMC breast oncologist Dr. Danielle Krol, who works with high-risk patients and personalizes her patients’ cancer screening recommendations and treatment plans.

Prior to joining JMC, Krol was the cancer prevention and risk reduction scientific expert for the Federal Drug Administration Oncology Center of Excellence and the National Cancer Institute as well an ABC News Medical Unit health care journalist in New York City.

Patients who are concerned about their hereditary cancer risk should first discuss their family history with their primary care physician or, for women, their gynecologist. If their personal or family history suggests an increased inherited cancer risk, they should be referred to a genetic counselor for a comprehensive risk assessment and discussion of appropriate genetic testing. If genetic testing identifies a pathogenic mutation or another clinically significant finding, the patient should then be referred to an oncologist to discuss personalized cancer screening, risk reduction strategies, and, if necessary, treatment recommendations. “Genetic counseling before testing is important,” Krol says. “It helps to identify the people most at risk.”

“Our counselors are skilled and specially trained and will share results with the patient and family,” Du Bois says. “We feel it’s appropriate to have counseling and the support that goes along with it. If it’s positive, it affects not only the patient but the family as well.”

SEARCHING FOR BIOMARKERS

Genetic testing and genomic testing are often confused, though they differ in scope. While traditional genetic testing typically examines a single gene, genomic testing analyzes all of a person’s genes or the genome within diseased cells, such as tumors.

The standard of care has evolved considerably over the past decade, Du Bois says. Previously, a biopsy of a suspicious mass would be sent to a lab, and the treatment would focus on eradicating the cancerous cells. But today, the standard approach for a tumor involves pathological evaluation of the tumor and also next-generation molecular testing. Du Bois explains “the molecular signature of the tumor guides more precise, targeted treatment decisions.” Next-generation sequencing (NGS) panels are now a cornerstone of precision oncology, used to identify actionable genomic alterations in a patient’s tumor that can be matched to specific targeted therapies or immunotherapies. “The fascinating part is that these panels simultaneously analyze hundreds of cancer-related genes in a single assay, detecting a wide range of alterations in genes including point mutations, insertions/deletions, and genomic signatures such as microsatellite instability (MSI), mismatch repair deficiency (dMMR), and tumor mutational burden (TMB),” he says. Medicine has never been so personalized.

Beyond tumors themselves, the blood can also reveal important indicators of cancer. “Many cancers will shed molecular evidence, or DNA, into the blood. A cancer’s unique genetic “fingerprint”, known as tumor-informed circulating tumor DNA (ctDNA), can detect small amounts of that specific tumor’s DNA through a simple blood draw, known as a “liquid biopsy.”

"When a repeat biopsy of a tumor is not feasible, blood-based testing can identify the molecular features of a cancer and what treatments may be best,” says Du Bois.

The growing emphasis on tumor and blood biomarkers is driving the development of precision treatments. Pembrolizumab (brand name Keytruda) is one example of this—it is a Food and Drug Administration (FDA)-approved immunotherapy, also known as a checkpoint inhibitor, used to treat dozens of types of early-stage and advanced cancer.

In May, the American Society of Clinical Oncology announced findings from a Phase III clinical trial demonstrating that a drug called daraxonrasib doubled the overall chance of survival in patients with previously treated metastatic pancreatic cancer compared to standard chemotherapy. The results were simultaneously published in the New England Journal of Medicine. Anna Berkenblit, MD, Chief Scientific and Medical Officer of the Pancreatic Cancer Action Network, described the results as a transformative chapter for a disease historically defined by few effective therapies and poor prognoses.

Daraxonrasib is an oral agent that targets a mutation found in over 90 percent of pancreatic cancers. According to Du Bois, the drug is better tolerated than conventional chemotherapy and is associated with improved quality of life for patients.

Expanded clinical trials are ongoing as the drug moves towards anticipated approval from the FDA. Studies will also explore draxonrasib’s effectiveness for patients with pancreatic cancer subtypes, and whether it can be used in earlier stages of the disease or in combination with other treatments.

The Pancreatic Cancer Action Network recommends biomarker testing for all patients with pancreatic cancer as it can guide treatment decisions and potentially open doors for more clinical trial opportunities.

Du Bois says this milestone not only represents treatment advancements, but also a deeper understanding of cancer biology. “It took decades to design a drug that targets this mutation; it turns the cell off and the cancer dies. In the near future, it won’t be important to know where a cancer came from but its molecular fingerprint,” he predicts. “It’s a new area that’s rapidly growing.”

RECOMMENDED GUIDELINES

There are a growing number of genomic and blood-based cancer detection tests being marketed to consumers that tap into the desire to detect cancer as early as possible While these tests are generating excitement, many are still being developed and not yet incorporated into routine screening recommendations from organizations such as the National Comprehensive Cancer Network.

Some cancer detection tests are intended for certain patients with specific clinical situations rather than for the general population.

One example is Signatera, a personalized blood test which detects molecular residual disease—tiny amounts of cancer cell DNA that may remain in the body after a patient has gone through treatment. Although Signatera has shown promise in identifying patients at higher risk of recurrence, its role in guiding treatment decisions is still being investigated. A positive result can create difficult questions. Should additional imaging be performed? Should treatment be changed?

“There are no clear guidelines for what to do next after a positive Signatera test,” Krol says. “The technology is promising, but it’s still relatively new, and we don’t yet have long-term data showing how acting on these results affects patient outcomes.”

It is important for patients to understand that there are no direct-to-consumer cancer blood tests that can diagnose or screen for multiple cancers that have been approved by the FDA, except for a few specifically targeting colorectal cancer, which require a physician’s prescription. Cologuard—an at-home colorectal cancer screening test for adults 45 and older—detects altered DNA and hidden blood in stool to identify early-stage cancer and precancerous polyps. If the results come back positive, the patient should visit a gastroenterologist and set up a colonoscopy appointment.

The American College of Gastroenterology and most oncologists, like Krol and Du Bois, emphasize that a colonoscopy remains the gold standard for the diagnosis of colorectal cancer screening. Cancerguard claims its test “helps detect over 50 types and subtypes of cancer” though a prominent disclaimer on its website homepage states: “This test is not a replacement for existing recommended cancer screening or diagnostic modalities for cancer.”

Krol, Du Bois, and leading medical organizations all agree and emphasize that evidence-based cancer care includes age appropriate screening, risk assessment, counseling, and a thorough evaluation by a physician. While blood-based cancer screening is rapidly advancing, an abnormal blood test does not necessarily tell us everything,” Krol says. “To confirm a diagnosis of cancer, we need tissue—whether that is from a mass that shows up on a mammogram, a lesion discovered during a colonoscopy, or an abnormal computed tomography (CT) scan of the chest.” Blood tests that check for multiple forms of cancer have their limitations and can also return with false negatives or false positives. “No blood test is 100 percent accurate,” Krol notes. Blood tests also do not show a cancer’s primary origin. For example, a tumor found in the liver may actually represent cancer that began in another organ and later spread. “A tissue biopsy is essential to confirm that cancer cells are present and to identify where the cancer started,” Krol says, information that is critical for selecting the most appropriate treatment.

“It’s exciting how oncology is advancing. The new technology is a remarkable step forward. They are not prime time, but they are evolving, and that’s exciting,” Krol says.